This review examined the effectiveness of phenobarbital and diazepam for the prophylaxis of febrile seizures in children. The authors stated that no conclusions could be drawn regarding the effectiveness of the two drugs, owing to the differing nature of the primary studies. Overall, the authors' conclusions are in line with the evidence reviewed and appear warranted.

Authors' objectives

To assess the effectiveness of phenobarbital and diazepam versus placebo for the prophylaxis of febrile seizures in children.

Searching

MEDLINE, LILACS and EMBASE were searched for studies published in English, Spanish or Portuguese; although the search terms were reported, the search dates were not. Additional sources were the Cochrane Centre of Brazil, references of included studies, theses indexed at BIREME/PAHO-WHO (Biblioteca Regional Medicina/Panamerican Health Organization of the World Health Organization) and abstracts sent to medical meetings. Experts were also contacted.

Study selection

Study designs of evaluations included in the review

Randomised double-blind placebo-controlled trials (RCTs) were eligible for inclusion. Trials that were reported as being randomised and double-blind for which there was contrary evidence regarding the methods of randomisation or blinding were excluded. Case reports were also excluded.

Specific interventions included in the review

Studies that assessed either intermittent diazepam or continuous phenobarbital compared with placebo were eligible for inclusion. The dose of diazepam in the included studies ranged from 0.2 to 0.65 mg/kg, the frequency of drug administration from 8/8 to 12/12 hours, and the duration of treatment from 10.3 to 24 months. The route of administration was rectal in two of the trials and oral in a further two. The dose of phenobarbital ranged from 3 to 5 mg/kg per day and the duration of treatment ranged from 3 to 24 months. The route of administration was oral in all of the trials.

Participants included in the review

No inclusion criteria were stated in relation to the participants. Studies that included children who had experienced previous febrile seizure were included.

Outcomes assessed in the review

No inclusion criteria were stated in relation to the outcomes. The specific outcomes assessed were the recurrence of febrile seizures or febrile convulsion. The included studies followed up participants for between 10.3 and 36 months.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

Study quality was assessed according to methods of randomisation and blinding. Studies that were reported as randomised and double-blind, and which described the methods of randomisation and blinding, were scored as level A; trials in which the methods were not described, but no evidence to the contrary regarding randomisation and blinding was presented, were scored as level B. The authors did not state how many reviewers performed the quality assessment.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data were abstracted on the number of febrile seizures or convulsions in each treatment arm, and the intermittent use of diazepam or continuous phenobarbital. The odds ratio (OR) and associated 95% confidence interval (CI) were calculated for each study.

Methods of synthesis

How were the studies combined?

The studies were combined using the method of Peto in a fixed-effect meta-analysis. Pooled ORs and the number-needed-to-treat (NNT), together with the respective 95% CIs, were calculated for several comparisons: intermittent diazepam versus placebo, continuous phenobarbitone versus placebo, and either active drug versus placebo.

How were differences between studies investigated?

Statistical differences between the studies were evaluated using funnel plot graphs and the chi-squared test (0.05 level of significance). Clinical differences between the studies, in terms of the participant populations, were briefly discussed in the text.

Results of the review

Eleven RCTs with a total of 1,722 participants were included. The analyses were based on 10 RCTs with a total of 1,527 participants.

Intermittent diazepam versus placebo (4 RCTs).

In the diazepam group, 11.2% (44 out of 393) had a recurrence of febrile convulsion compared with 17.1% in the placebo group (68 out of 398); the OR was 0.6 (95% CI: 0.40, 0.90) in favour of treatment with diazepam. The NNT was 17 (95% CI: 10, 85). Significant statistical heterogeneity was observed in the trials (chi-squared 10.19, P<0.01).

Phenobarbital versus placebo (6 RCTs).

In the phenobarbital group, 24.5% (71 out of 290) experienced a recurrence of febrile convulsion compared with 37.0% (114 out of 308) of the placebo group; the OR was 0.54 (95% CI: 0.38, 0.76) in favour of treatment with phenobarbital. The NNT was 8 (95% CI: 5, 18). Significant statistical heterogeneity was observed in the trials (chi-squared 15.40, P<0.01).

Intermittent diazepam or phenobarbital versus placebo (10 RCTs).

The OR for recurrence of febrile convulsion with either intermittent diazepam or phenobarbital versus placebo was 0.56 (95% CI: 0.43, 0.73) in favour of active treatment. The NNT was 12 (95% CI: 8, 22). Significant statistical heterogeneity was observed across the trials (chi-squared 25.76, P=0.0022).

Authors' conclusions

The authors concluded that there was not a strong recommendation to treat febrile seizure either with continuous phenobarbital or with intermittent diazepam prophylaxis, owing to the design and heterogeneity of the primary studies.

CRD commentary

The review question was defined only in terms of the interventions and study design. No inclusion criteria were stated in relation to the participants or the outcome measures of interest. A number of sources were searched for both published and unpublished studies, but no search dates were reported; it is therefore not possible to comment on how comprehensive the electronic searches were. The methods of undertaking the review were not reported, thus it is not known whether any steps were taken to minimise reviewer bias and errors. The quality of the primary studies was partially assessed, but this was only based upon the methods of and level of reporting of randomisation and blinding. Other important methodological aspects of the included trials were, therefore, not assessed.

Only minimal information on the included studies was provided. It was therefore not possible for the reader to assess whether the studies were similar enough, in terms of participant populations and methodological quality, for the pooling to be considered appropriate. The use of a meta-analysis to combine the studies was not appropriate from a statistical viewpoint. Further exploration of the sources of heterogeneity would have been useful. Overall, the authors' conclusions that the effectiveness of phenobarbital and diazepam could not be demonstrated would appear warranted.

Implications of the review for practice and research

Practice: The authors stated that any treatment decision should arise from the appropriate judgement and experience of the physician.

Research: The authors stated that a standard trial with a large number of patients should be conducted to assess the effectiveness of both intermittent diazepam and phenobarbital.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.